This K24 application is to support my career development as I build a translational research program. I am an associate professor, seeing patients with melanoma and renal cell carcinoma. I mentor junior faculty and clinical fellows and run an R-01 funded research laboratory, conducting biomarker studies and pre-clinical drug testing experiments in these two diseases. I have a busy clinical practice and actively enroll patients on clinical trials. Given the increased incidence of metastatic melanoma and the high frequency of brain metastases (BrMs) in this population, there is urgent need for new approaches to this problem, as most clinical trials exclude BrMs patients, and their therapeutic options are exceedingly limited. I recently assembled a group of clinical and basic science researchers that focus on BrMs, and my vision (and long term goal) is to develop a brain metastasis research center at Yale. My short term goal is to conduct our first two BrMs-specific protocols and to generate preclinical data for future trials. To accomplish my goals, I need additional protected time to conduct these studies and mentor junior clinicians to participate these efforts. My proposed career development plan includes both acquisition of new skills and a plan for increased mentorship of junior faculty and clinical fellows. The former involves formal training such as a didactic statistics course and informal training in animal experiments and additional training in development of phase I trials. In addition to mentorship of fellows, I will mentor junior faculty, including two current mentees and two new hires. I will participate in specific mentorship activities at Yale supported by the CTSA grant, including advisory committees and lectures. The underlying premise of this proposal is that drug penetration through the leaky vessels found in BrMs can be superior to typical BBB penetration. We further hypothesize that use of combinations of local therapies and molecular targeted therapies selected based on individual tumor characteristics will result in improved survival of patients wit BrMs, similar to patients with other visceral metastases. Finally, manipulation of brain immunity might be a means of treating brain metastases. My first aim includes the first neoadjuvant clinical trial using a targeted therapy (vemurafenib) and innovative surgical approaches to treat patients with brain metastases not amenable to gamma-knife therapy. Predictive biomarker studies will be incorporated, complimented by lab-based endeavors to train mentees in conducting pre-clinical drug sensitivity studies with an emphasis on BrMs, with the goal of developing a pipeline of drugs to be studied in future BrM trials. In aim 2, I will mentor a junior faculty clinician in conducting a clinical trial of an antibody against an immune-checkpoint inhibitory molecule (PD-1), and development of a panel of predictive biomarkers.